EP2725042A1 - Polymer und verfahren zu seiner herstellung - Google Patents
Polymer und verfahren zu seiner herstellung Download PDFInfo
- Publication number
- EP2725042A1 EP2725042A1 EP12803914.6A EP12803914A EP2725042A1 EP 2725042 A1 EP2725042 A1 EP 2725042A1 EP 12803914 A EP12803914 A EP 12803914A EP 2725042 A1 EP2725042 A1 EP 2725042A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- polymer
- formula
- represented
- reaction
- mpc
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 229920000642 polymer Polymers 0.000 title claims abstract description 84
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 239000012756 surface treatment agent Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 22
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 238000006116 polymerization reaction Methods 0.000 claims description 9
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 3
- RITDWOLPOPICQM-UHFFFAOYSA-N CC(C(OCCC(COP([O-])(O)=O)[N+](C)(C)C)=O)=C Chemical compound CC(C(OCCC(COP([O-])(O)=O)[N+](C)(C)C)=O)=C RITDWOLPOPICQM-UHFFFAOYSA-N 0.000 claims description 2
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 7
- 230000003013 cytotoxicity Effects 0.000 abstract description 7
- 238000012545 processing Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 22
- 125000003277 amino group Chemical group 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000001179 sorption measurement Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- PGSADBUBUOPOJS-UHFFFAOYSA-N neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000005259 measurement Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000178 monomer Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- 239000004698 Polyethylene Substances 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229920000573 polyethylene Polymers 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 239000006143 cell culture medium Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- -1 2-amidinopropyl Chemical group 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 150000002500 ions Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 4
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 description 4
- LXEKPEMOWBOYRF-UHFFFAOYSA-N [2-[(1-azaniumyl-1-imino-2-methylpropan-2-yl)diazenyl]-2-methylpropanimidoyl]azanium;dichloride Chemical compound Cl.Cl.NC(=N)C(C)(C)N=NC(C)(C)C(N)=N LXEKPEMOWBOYRF-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 239000007870 radical polymerization initiator Substances 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- 239000002033 PVDF binder Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000006285 cell suspension Substances 0.000 description 3
- 231100000263 cytotoxicity test Toxicity 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- 239000012460 protein solution Substances 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000001226 reprecipitation Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 238000004381 surface treatment Methods 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000002612 cardiopulmonary effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 125000003700 epoxy group Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000008569 process Effects 0.000 description 2
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- 239000011780 sodium chloride Substances 0.000 description 2
- 239000004317 sodium nitrate Substances 0.000 description 2
- 235000010344 sodium nitrate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- OPQYOFWUFGEMRZ-UHFFFAOYSA-N tert-butyl 2,2-dimethylpropaneperoxoate Chemical compound CC(C)(C)OOC(=O)C(C)(C)C OPQYOFWUFGEMRZ-UHFFFAOYSA-N 0.000 description 2
- NMOALOSNPWTWRH-UHFFFAOYSA-N tert-butyl 7,7-dimethyloctaneperoxoate Chemical compound CC(C)(C)CCCCCC(=O)OOC(C)(C)C NMOALOSNPWTWRH-UHFFFAOYSA-N 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- FVQMJJQUGGVLEP-UHFFFAOYSA-N (2-methylpropan-2-yl)oxy 2-ethylhexaneperoxoate Chemical compound CCCCC(CC)C(=O)OOOC(C)(C)C FVQMJJQUGGVLEP-UHFFFAOYSA-N 0.000 description 1
- OCNODTCSMUUTNC-UHFFFAOYSA-N (4-hydroxy-2-methylpentan-2-yl) 2,2-dimethylpropaneperoxoate Chemical compound CC(O)CC(C)(C)OOC(=O)C(C)(C)C OCNODTCSMUUTNC-UHFFFAOYSA-N 0.000 description 1
- RQHGZNBWBKINOY-PLNGDYQASA-N (z)-4-tert-butylperoxy-4-oxobut-2-enoic acid Chemical compound CC(C)(C)OOC(=O)\C=C/C(O)=O RQHGZNBWBKINOY-PLNGDYQASA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- OALMZWNBNXQUAL-UHFFFAOYSA-N 2-[(1-amino-2-methyl-1-oxopropan-2-yl)diazenyl]-2-methylpropanamide Chemical compound NC(=O)C(C)(C)N=NC(C)(C)C(N)=O OALMZWNBNXQUAL-UHFFFAOYSA-N 0.000 description 1
- MYECVPCGFLCGQX-UHFFFAOYSA-N 2-[(1-amino-2-methyl-1-phenyliminopropan-2-yl)diazenyl]-2-methyl-n'-phenylpropanimidamide;dihydrochloride Chemical compound Cl.Cl.C=1C=CC=CC=1NC(=N)C(C)(C)N=NC(C)(C)C(=N)NC1=CC=CC=C1 MYECVPCGFLCGQX-UHFFFAOYSA-N 0.000 description 1
- AZCYBBHXCQYWTO-UHFFFAOYSA-N 2-[(2-chloro-6-fluorophenyl)methoxy]benzaldehyde Chemical compound FC1=CC=CC(Cl)=C1COC1=CC=CC=C1C=O AZCYBBHXCQYWTO-UHFFFAOYSA-N 0.000 description 1
- VUDVPVOIALASLB-UHFFFAOYSA-N 2-[(2-cyano-1-hydroxypropan-2-yl)diazenyl]-3-hydroxy-2-methylpropanenitrile Chemical compound OCC(C)(C#N)N=NC(C)(CO)C#N VUDVPVOIALASLB-UHFFFAOYSA-N 0.000 description 1
- WYGWHHGCAGTUCH-UHFFFAOYSA-N 2-[(2-cyano-4-methylpentan-2-yl)diazenyl]-2,4-dimethylpentanenitrile Chemical compound CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C WYGWHHGCAGTUCH-UHFFFAOYSA-N 0.000 description 1
- QLIBJPGWWSHWBF-UHFFFAOYSA-N 2-aminoethyl methacrylate Chemical compound CC(=C)C(=O)OCCN QLIBJPGWWSHWBF-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- IXHVFQAWXRNZCZ-UHFFFAOYSA-N 2-methyl-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]peroxypropanoic acid Chemical compound CC(C)(C)OC(=O)C(C)(C)OOC(C)(C)C(O)=O IXHVFQAWXRNZCZ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- VFXXTYGQYWRHJP-UHFFFAOYSA-N 4,4'-azobis(4-cyanopentanoic acid) Chemical compound OC(=O)CCC(C)(C#N)N=NC(C)(CCC(O)=O)C#N VFXXTYGQYWRHJP-UHFFFAOYSA-N 0.000 description 1
- MKTOIPPVFPJEQO-UHFFFAOYSA-N 4-(3-carboxypropanoylperoxy)-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)OOC(=O)CCC(O)=O MKTOIPPVFPJEQO-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
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- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
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- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
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- WTNTZFRNCHEDOS-UHFFFAOYSA-N n-(2-hydroxyethyl)-2-methylpropanamide Chemical compound CC(C)C(=O)NCCO WTNTZFRNCHEDOS-UHFFFAOYSA-N 0.000 description 1
- QYZFTMMPKCOTAN-UHFFFAOYSA-N n-[2-(2-hydroxyethylamino)ethyl]-2-[[1-[2-(2-hydroxyethylamino)ethylamino]-2-methyl-1-oxopropan-2-yl]diazenyl]-2-methylpropanamide Chemical compound OCCNCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCNCCO QYZFTMMPKCOTAN-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L persulfate group Chemical group S(=O)(=O)([O-])OOS(=O)(=O)[O-] JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- BWJUFXUULUEGMA-UHFFFAOYSA-N propan-2-yl propan-2-yloxycarbonyloxy carbonate Chemical compound CC(C)OC(=O)OOC(=O)OC(C)C BWJUFXUULUEGMA-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- YRSOBOMBMPSGBZ-UHFFFAOYSA-N sodium;1,3,5-trinitrobenzene Chemical compound [Na].[O-][N+](=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 YRSOBOMBMPSGBZ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F230/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F230/02—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F130/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
- C08F130/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing phosphorus
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
- C08F220/36—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate containing oxygen in addition to the carboxy oxygen, e.g. 2-N-morpholinoethyl (meth)acrylate or 2-isocyanatoethyl (meth)acrylate
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/38—Esters containing sulfur
- C08F220/387—Esters containing sulfur and containing nitrogen and oxygen
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
- C08F220/32—Esters containing oxygen in addition to the carboxy oxygen containing epoxy radicals
- C08F220/325—Esters containing oxygen in addition to the carboxy oxygen containing epoxy radicals containing glycidyl radical, e.g. glycidyl (meth)acrylate
Definitions
- the present invention relates to a novel polymer that is useful for imparting biocompatibility to medical devices which come into contact with living tissues, a method for producing the same, and a surface treatment agent for medical devices utilizing the polymer.
- Patent Publication 2 proposes use of a copolymer of 2-methacryloyloxyethyl-2-trimethylammonioethyl phosphate (abbreviated as MPC hereinbelow) and allylamine (abbreviated as AAM hereinbelow) on medical device surfaces for improved biocompatibility.
- MPC 2-methacryloyloxyethyl-2-trimethylammonioethyl phosphate
- AAM allylamine
- AAM is highly toxic and inconvenient in handling, so that it is not preferred to increase the compositional ratio of AAM in the copolymer.
- Patent Publication 3 proposes reacting MPC copolymer having primary amino groups, which is obtained by copolymerization of MPC and 2-aminoethylmethacrylate (abbreviated as AEMA hereinbelow), with reactive surfaces of medical devices. According to this method, the copolymer having highly reactive amino groups is chemically bonded to medical device surfaces, so that an increased amount of amino groups are introduced, resulting in highly durable surfaces.
- AEMA 2-aminoethylmethacrylate
- cationic property of the functional groups remaining unreacted may cause protein adsorption, activation of immune cells, or adsorption to cells, which may deteriorate the biocompatibility.
- the present inventors have made intensive researches in the light of the above objects to find out that reaction of a particular polymer having a phosphorylcholine-like group with 2-aminoethanethiol yields a polymer that is capable of improving surface hydrophilicity of medical devices, and has high biocompatibility and low cytotoxicity even when its reactivity to surfaces is low, to thereby complete the present invention.
- a polymer comprising structural units represented by the formulae (1a) and (1b), and having a weight average molecular weight of 10000 to 5000000:
- a method for producing this polymer comprising polymerization of a monomer composition comprising MPC presented by the formula (2a) and glycidyl methacrylate represented by the formula (2b) (abbreviated as GMA hereinbelow) at a molar ratio of GMA being 5 to 30 % of a total amount of MPC and GMA, followed by reaction with 2-aminoethanethiol represented by the formula (3) (abbreviated as AET hereinbelow): HS-CH 2 -CH 2 -NH 2 Formula (3).
- a surface treatment agent for a medical device consisting of an aqueous solution comprising 0.1 to 20 mass% of the polymer.
- the polymer according to the present invention having the structure mentioned above, capable of imparting hydrophilicity and biocompatibility to medical device surfaces by simple processing, and having low cytotoxicity, is useful as a surface treatment agent for medical devices which come into contact with body fluid or blood, such as guidewires, catheters, artificial vessels, cardiopulmonary bypasses, contact lenses, and intraocular lenses.
- the polymer according to the present invention has structural units represented by the formulae (1a) and (1b) above and a weight average molecular weight of 10000 to 5000000, preferably 100000 to 1500000, and may optionally have a structural unit or units other than those represented by the formulae (1a) and (1b).
- a weight average molecular weight of less than 10000 adhesivity to medical device surfaces is not sufficient, which may cause inferior durability
- a weight average molecular weight of over 5000000 viscosity of the polymer during its production is too high, which may cause difficulties in handling.
- b/(a+b) is less than 5
- adhesivity to medical device surfaces is not sufficient, durability may be low, and surface hydrophilicity may not be improved.
- b/(a+b) is over 30, cytotoxicity may be high.
- the polymer of the present invention may be obtained, for example, by the method of the present invention wherein a monomer composition containing MPC represented by the formula (2a) and GMA represented by the formula (2b) at the molar ratio of GMA being 5 to 30 % of the total amount of MPC and GMA, is polymerized, and then reacted with AET represented by the formula (3).
- the polymerization of the monomer composition may be carried out, for example, in the presence of a radical polymerization initiator in an atmosphere of or substituted with an inert gas, such as nitrogen, carbon dioxide, argon, or helium, by a known method, for example radical polymerization, such as bulk, suspension, emulsion, or solution polymerization. In view of purification or the like of the resulting polymer, solution polymerization is preferred.
- a polymer having a structural unit represented by the formula (2) is obtained:
- the radical polymerization initiator may be an azo radical polymerization initiator, such as 2,2-azobis(2-amidinopropyl) dihydrochloride, 2,2-azobis(2-(5-methyl-2-imidazoline-2-il)propane) dihydrochloride, 4,4-azobis(4-cyanovaleric acid), 2,2-azobisisobutylamide dihydrate, 2,2-azobis(2,4-dimethylvaleronitrile), 2,2-azobisisobutylonitrile (AIBN), dimethyl-2,2'-azobisisobutylate, 1-(1-cyano-1-methylethyl)azo) formamide, 2,2'-azobis(2-methyl-N-phenylpropionamidine) dihydrochloride, 2,2'-azobis(2-methyl-N-(2-hydroxyethyl)-propionamide, 2,2'-azobis(2-methylpropionamide) dehydrate, 4,4'-azobis(4-cyanopentanoic acid), or 2,2'-azobis(
- organic peroxides may also be used, such as benzoyl peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, t-butyl peroxypivalate, t-butyl peroxydiisobutyrate, lauroyl peroxide, t-butyl peroxyneodecanoate, succinylperoxide, glutarperoxide, succinyl peroxyglutarate, t-butyl peroxymaleate, t-butyl peroxypivalate, di-2-ethoxyethyl peroxycarbonate, or 3-hydroxy-1,1-dimethylbutyl peroxypivalate.
- benzoyl peroxide diisopropyl peroxydicarbonate
- t-butylperoxy-2-ethylhexanoate t-butyl peroxypivalate
- persulfates may also be used, such as ammonium persulfate, potassium persulfate, or sodium persulfate.
- persulfates such as ammonium persulfate, potassium persulfate, or sodium persulfate.
- One or a mixture of these radical polymerization initiators may be used.
- the amount of the polymerization initiator is usually 0.001 to 10 parts by mass, preferably 0.01 to 5.0 parts by mass with respect to 100 parts by mass of the monomer composition.
- the polymerization of the monomer composition may be carried out in the presence of a solvent.
- the solvent may be selected from those which dissolve the monomer composition without reacting therewith, for example, water; alcohol solvents, such as methanol, ethanol, n-propanol, or isopropanol; ketone solvents, such as acetone, methyl ethyl ketone, or diethyl ketone; ester solvents, such as ethyl acetate; straight or cyclic ether solvents, such as ethyl cellosolve, tetrahydrofuran, or N-methylpyrrolidone; or nitrogen-containing solvents, such as acetonitrile, or nitromethane.
- Preferred is water, alcohol, or a mixed solvent thereof.
- the resulting polymer represented by the formula (2) may be used in the next reaction after purification or dilution of the polymerization solvent without further processing.
- the reaction of the polymer represented by the formula (2), which is obtained through polymerization of the monomer composition, with AET represented by the formula (3) may be carried out in a solvent under heating.
- the resulting polymer represented by the formula (1) may be purified by a common process, such as reprecipitation, dialysis, or ultrafiltration.
- the solvent may be selected from those which dissolve the polymer of the formula (2) and AET without reacting therewith, for example, protic solvents, such as methanol, ethanol, n-propanol, or isopropanol, with n-propanol being preferred for its reactivity.
- protic solvents such as methanol, ethanol, n-propanol, or isopropanol, with n-propanol being preferred for its reactivity.
- the solution concentration of the polymer of the formula (2) upon reaction is preferably 4 to 30 mass%. At over 30 mass%, viscosity of the reaction solution is high and the reaction may not proceed sufficiently. At less than 4 mass%, the amount of the reaction solvent is large and the production efficiency may be low.
- the amounts of the polymer of the formula (2) and AET are preferably such that the molar ratio of the epoxy groups in the polymer of the formula (2) to AET is 1 : 3 to 100.
- the molar ratio of AET over 100 is not economical, whereas the molar ratio of AET less than 3 may cause side reaction, and the desired water-soluble polymer may not result.
- reaction hitherto discussed may be carried out either by adding AET to the polymer of the formula (2) or by adding the polymer of the formula (2) to AET.
- AET may be dissolved in the solvent prior to the addition, or may be added as it is.
- gradual addition of AET may cause side reaction, and the desired water-soluble polymer may not result, and thus addition in a lump is preferred.
- the reaction temperature is preferably 40 to 100 °C. At less than 40 °C, the reaction may not proceed sufficiently, whereas at over 100 °C, the resulting polymer may decompose.
- the reaction time is preferably not less than 3 hours and not more than 48 hours. With less than 3 hours, control of the reaction may be hard, whereas with over 48 hours, side reaction may occur, resulting in low purity of the obtained polymer.
- reaction vessel substituted with an inert gas, such as nitrogen or argon, so that the thiol group in AET is prevented from being oxidized into disulfide.
- an inert gas such as nitrogen or argon
- the obtained reaction liquid may be purified by a common process, such as reprecipitation, dialysis, or ultrafiltration, to obtain the objective polymer of the formula (1).
- the surface treatment agent for medical devices according to the present invention is composed of an aqueous solution containing 0.1 to 20 mass% of the polymer of the present invention. At the polymer content of the aqueous solution of less than 0.1 mass%, reactivity with the medical device surface is low, whereas at over 20 mass%, the viscosity of the aqueous solution is too high, which may cause difficulties in handling.
- the surface treatment agent for medical devices according to the present invention may be used, for example, by application to a medical device surface or by immersion of a medical device in the surface treatment agent for medical devices, to thereby fix the polymer of the present invention.
- the fixing may be effected, for example, by covalent bonding, ion bonding, or coordinate bonding the polymer of the present invention to a medical device surface. In view of durability, covalent bonding is preferred.
- a covalent bond may be established, for example, by causing a functional group which is reactive to the amino group in the present polymer, to be present on a medical device surface, and covalently bonding these groups.
- the functional group may be, for example, a carboxyl, carboxylic acid anhydride, epoxy, or isocyanate group.
- the surface may be converted to have functional groups by means of a polyfunctional reagent, such as diisocyanate or diepoxy, to render the surface reactive to the amino group.
- the surface of the medical device may be treated with plasma, corona, or ozone to provide the surface with, for example, carboxyl groups, to thereby render the surface reactive to the amino group.
- the covalent bond may be established by suitably selecting the conditions from conventional ones, depending on the kind and amount of the functional group, the material from which the medical device is made, or the like.
- the medical device to which the surface treatment agent of the present invention is applied may be those which come into contact with body fluid or blood, such as guidewires, catheters, artificial vessels, cardiopulmonary bypass, contact lenses, and intraocular lenses.
- TNBS 2,4,6-trinitrobenzene sodium sulfonate
- the measurement was made of 5 mg of the obtained polymer dissolved in 1g of a 0.1 mol/L sodium nitrate aqueous solution.
- the remaining conditions for the measurement were as follows:
- Cytotoxicity was tested with reference to ISO10993-5: 2009 and N. Tani et al., Toxicology in vitro 13(1999), 175-187 , and evaluated based on the cell survival rate.
- DMEM Dulbecco's modification of Eagle's medium
- 100x an antibiotic/antifungal solution
- PVDF polyvinylidene fluoride
- a sterile petri dish 9 mL of the cell culture medium and 1 mL of a cell suspension were placed, and cultured in a CO 2 incubator for over 48 hours to proliferate the cells.
- the cells in the petri dish were microscopically observed to confirm cell count increase and the state of the cells (whether the cells were not killed or floating without being adhered).
- the cell suspension was adjusted to the concentration of 1 ⁇ 10 5 cells/mL with the cell culture medium.
- the adjusted cell suspension was dispensed into a 96-well plate at 100 ⁇ L/well with a micropipette, and incubated for 24 hours in a CO 2 incubator.
- the polymer sample and sodium lauryl sulfate (SLS) of biochemical grade as a positive control were each dissolved in the cell culture medium or Dulbecco's phosphate-buffered saline (PBS) (10x), and sterilized through a PVDF sterilizing filter (0.22 ⁇ m).
- the polymer solution thus prepared (test sample) was serially diluted on a 96-well plate.
- test sample of 1.0 mass% polymer content prepared above was added at 100 ⁇ L to the 24-hour-incubated 96-well plate for exposure in a CO 2 incubator for 24 hours.
- NR was dissolved in ion-exchanged water at 5 mg/mL to prepare a NR stock solution.
- the NR stock solution was diluted by 100 folds with the cell culture medium to prepare a NR medium.
- the 96-well plate exposed to the test sample was taken out, the medium was discharged into a basin, and the plate was patted on Kimtowel to remove the residual medium.
- the NR medium was added to the 96-well plate at 100 ⁇ L/well with a micropipette, and incubated in a CO 2 incubator for 3 hours to allow the cells to take in NR.
- the 96-well plate was taken out of the CO 2 incubator, and the NR medium was removed. PBS was added at 100 ⁇ L/well, and then removed. A NR extractant containing 50 mass% ethanol, 49 mass% ion exchanged water, and 1 mass% acetic acid was added at 100 ⁇ L/well with a micropipette, and shaken with a shaking apparatus for five minutes to extract NR from the cells. The absorption at 540 nm was determined with a plate reader.
- the SLS contact concentration at 50% cell survival rate was confirmed to be about 0.01 mass%, and the survival rate of the cells when treated with the test sample was calculated:
- Cell survival rate ( Absorption when treated with test sample - Absorption of blank ) / Absorption when treated with medium - Absorption of blank ⁇ 100
- a 1 ⁇ 4 cm polyethylene film was placed between the electrodes of a corona discharge device with the electrode interval of 3 cm at a voltage across the electrodes of 15 kV to effect a discharge treatment. Then the film was immersed in a 10 mass% methacrylic acid aqueous solution, deaerated, and subjected to graft polymerization in vacuum. After the polymerization, the film was thoroughly washed with water, to obtain a MAA-grafted PE film.
- the 1 x 4 cm MAA-grafted PE film prepared above was immersed in 4.0 g of a 5 mass% aqueous solution of the polymer prepared in each Example or Comparative Example to be discussed later, also containing 0.04 g of water-soluble carbodiimide, to effect coupling reaction at room temperature for 24 hours. After this treatment, the film was washed with water, to thereby obtain a polymer-grafted film, which was subjected to the following evaluations.
- the film surface was analyzed by XPS, and the amount of the adhered polymer was calculated.
- the polymer-grafted film which had been immersed in water, was drawn out of the water, and the time lapsed before the water film was broken was measured to evaluate the surface hydrophilicity. The evaluation was made as follows:
- the solution thus prepared was mixed with 100 mL of acetonitrile to give an extractant liquid.
- the polymer had a weight average molecular weight of 630000, and the ratio of the units derived from MPC of the formula (1a) was 80 mol%, and the ratio of the units derived from the amino group of the formula (1b) was 20 mol%.
- the polymer had a weight average molecular weight of 850000, and the ratio of the units derived from MPC of the formula (1a) was 70 mol%, and the ratio of the units derived from the amino group of the formula (1b) was 30 mol%.
- Example 1-1 The reactions in Example 1-1 were followed, except that the monomers, the solvent, and the initiator were replaced with those shown in Table 1.
- the obtained polymer was subj ected to the measurements in the same way as in Example 1-1. The results are shown in Table 1.
- the polymers of Examples 1-1 to 1-4 had higher cell survival rates than the polymers of Comparative Examples 1-2 to 1-4, and were demonstrated to be safe. Further, comparing the results of the surface treatment tests, the polymers of Examples 1-1 to 1-4 were demonstrated to have hydrophilic film surface and suppressed protein adsorption, compared to the polymers of Comparative Examples 1-1 and 1-5.
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
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JP6248603B2 (ja) * | 2013-12-17 | 2017-12-20 | 日油株式会社 | ポリマー及びその製造方法 |
US10323132B2 (en) * | 2015-03-03 | 2019-06-18 | Nof Corporation | Polymer and crosslinked body thereof |
TWI748993B (zh) * | 2016-02-23 | 2021-12-11 | 日商日油股份有限公司 | 軟式隱形眼鏡用溶液在抑制蛋白質附著於軟式隱形眼鏡中的用途 |
EP3655448A1 (de) | 2017-07-18 | 2020-05-27 | Alcon Inc. | Phosphorylcholin enthaltende poly(meth)acrylamid-basierte copolymere |
US10920099B2 (en) | 2017-07-18 | 2021-02-16 | Alcon Inc. | Poly(meth)acrylamide-based copolymers with carboxyl-terminated pendant chains |
EP3724697B1 (de) | 2017-12-13 | 2022-01-12 | Alcon Inc. | Verfahren zur herstellung von mps-kompatiblen kontaktlinsen mit wassergradient |
WO2020115570A1 (en) | 2018-12-03 | 2020-06-11 | Alcon Inc. | Method for making coated silicone hydrogel contact lenses |
SG11202104402PA (en) | 2018-12-03 | 2021-06-29 | Alcon Inc | Method for coated silicone hydrogel contact lenses |
WO2020208576A1 (en) | 2019-04-10 | 2020-10-15 | Alcon Inc. | Method for producing coated contact lenses |
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- 2012-06-12 JP JP2013522572A patent/JP5871000B2/ja active Active
- 2012-06-12 EP EP12803914.6A patent/EP2725042B1/de active Active
- 2012-06-12 KR KR1020147000608A patent/KR101851825B1/ko active IP Right Grant
- 2012-06-12 CN CN201280029385.3A patent/CN103596996B/zh active Active
- 2012-06-12 WO PCT/JP2012/065040 patent/WO2013002021A1/ja active Application Filing
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US6653423B1 (en) * | 1999-07-14 | 2003-11-25 | Nof Corporation | Random copolymers, process for the production thereof and medical material |
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Also Published As
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US20140142240A1 (en) | 2014-05-22 |
JP5871000B2 (ja) | 2016-03-01 |
EP2725042B1 (de) | 2018-08-29 |
KR101851825B1 (ko) | 2018-04-24 |
EP2725042A4 (de) | 2014-11-05 |
CN103596996B (zh) | 2015-11-25 |
JPWO2013002021A1 (ja) | 2015-02-23 |
TW201302820A (zh) | 2013-01-16 |
TWI526458B (zh) | 2016-03-21 |
KR20140041705A (ko) | 2014-04-04 |
WO2013002021A1 (ja) | 2013-01-03 |
US9127099B2 (en) | 2015-09-08 |
CN103596996A (zh) | 2014-02-19 |
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